Epilepsy is a complex neurological disorder that affects ˜50 million people worldwide. The lifetime prevalence is ˜1%, and it affects individuals of all ages regardless of gender or socio-economic status. Epilepsy can be acquired as a result of an insult to the brain such as trauma, infection, stroke or a tumour, or can result from a genetic mutation in one or more of the ion channel or neurotransmitter genes or proteins that control brain excitability (Bialer et al. Nat. Rev. Drug Discov. 2010, 9:68-82).
Epileptic seizures can be generalized (generalized epileptic seizure), originating in both hemispheres of the brain simultaneously, or partial (focal seizures) originating in one or more parts of one or both hemispheres, most commonly the temporal lobe. With generalized seizures, consciousness is always impaired or lost. Consciousness may be maintained in partial seizures but partial seizures may become generalized seizures in a process referred to as secondary generalization, at which point consciousness is lost. In patients the type of epilepsy or epileptic syndrome are further classified according to features such as the type of seizure, etiology, age of onset and electroencephalogram. Epilepsy or epileptic syndromes can be either idiopathic (etiology or cause is unknown) with a presumed genetic basis or symptomatic (acquired). The known potential causes of epilepsy include brain tumors, infections, traumatic head injuries, perinatal insults, developmental malformations, cerebrovascular diseases, febrile seizures and status epilepticus (Loscher, Trends Pharmacol. Sci, 2002, 23:113-118).
Despite progress in understanding the pathogenesis of epileptic seizures, the cellular basis of human epilepsy remains a mystery and, in the absence of specific etiological comprehension, approaches to drug therapy are still directed toward the control of symptoms, i.e., suppression of seizures. Chronic administration of antiepileptic drugs (AEDs) is the treatment of choice in epilepsy (Dreyfuss et al. Handbook of Experimental Pharmacology; Springer: Berlin, 1999; 1-15).
The past decade witnessed considerable progress in the pharmacotherapy of epilepsy, including the introduction of several new AEDs and improved formulations of older, “first-generation” drugs, such as phenytoin, carbamazepine, phenobarbital, and valproate. Newer “second-generation” drugs include lamotrigine, vigabatrin, tiagabine, topiramate, oxcarbazepine, zonisamide, gabapentin, and levetiracetam. However, only a minority of patients refractory to first-generation AEDs are reported to be seizure-free with second-generation AEDs.
A number of clinical anticonvulsants including phenytoin, carbamazepine, lamotrigine, gabapentin and pregabalin are widely utilized in the management of neuropathic pain (Collins et al. Expert Opinion Emerging Drugs, 2005, 10:95-108). Neuropathic pain results from a cascade of neurobiological events, which tend to induce electrical hyper excitability within somatosensory conduction pathway. Since electrical hyper excitability is also the hallmark of epileptic seizure activity, anticonvulsants are among the first agents adopted in the treatment of neuropathic pain and remain the first option in clinical use.
Pain is both a sensory and emotional experience, and is generally associated with tissue damage or inflammation. Typically, pain is divided into two general categories—acute pain and chronic pain. Both differ in their etiology, pathophysiology, diagnosis, and most importantly treatment.
Acute pain is short term, and is typically of readily identifiable cause. Patients suffering from acute pain typically respond well to medications. In contrast, chronic pain—medically defined as pain that lasts for 3-6 months or longer, is often not associated with any obvious injury; indeed, patients can suffer from protracted pain that persists for months or years after the initial insult. Whilst acute pain is generally favorably treated with medications, chronic pain is often much more difficult to treat, generally requiring expert care. Few, if any, ethical drugs have been prospectively developed for the treatment of chronic pain. Instead, the current medications used to treat chronic pain are “borrowed” from other diseases, most commonly antiepileptic drugs and antidepressants.
Current first-line treatments for chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. When opioids are administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur. Of treatment remedies currently available for chronic pain, at best approximately 30% are effective in significantly diminishing the pain, and these can lose their efficiency over time.
In instances in which treatment with a single agent proves to be unsuccessful, combination therapy is often then explored as a second line treatment. For example, such combination therapy may employ administration of an opioid agent with an adjuvant analgesic, although the relative doses of each are often subject to prolonged trial and error periods. Often, triple drug therapy is necessary. Such therapy generally involves a combination of tricyclic antidepressants, anticonvulsants and a systemic local anesthetic. Patient compliance drops significantly, however, when treatment requires the administration of multiple pharmacologic agents. Recently, researchers reported the use of a combination of morphine and gabapentin in a randomized study for controlling nerve pain (Gilron, et al., N. Eng. J. Med., 2005, 352:1281-82).
In treatment, it is important to consider overall pain relief, as well as the type of pain relief. For example, chronic pain is typically viewed as allodynia or hyperalgesia. Allodynia is pain sensation from a stimulus which is not normally painful. Allodynia is typically caused by a physical stimulus and is thus referred to as tactile or mechanical allodynia. Hyperalgesia is an exaggerated sensation form a stimulus which is normally painful. The hyperalgesia can occur from a variety of stimuli but, commonly, a patient's reaction to hot or cold stimuli is reported.
Neuropathic pain (NP) is generally thought of as a maladaptive chronic condition in which pain originates from damaged nerves, often yielding pain that is out of proportion to the extent of any injury. Damage can occur from a physical injury such as trauma or from chemical injury such as chemotherapeutics (e.g. paclitaxel). Neuropathic pain of this type is an important component of a number of syndromes of varying etiologies whose common characteristic is the development of a prolonged and profound pain state. Among these conditions are spinal cord injury, post-herpetic neuralgia, diabetic neuropathy, phantom limb pain, stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia, complex regional pain syndrome (CRPS), chemotherapy-induced neuropathic pain, vertebral disk rapture, trigeminal neuralgia and others.
Recently, it has been recognized that neuropathic pain can also manifest itself in the absence of an identifiable nerve injury. These indications include AIDS and mirror image pain. The lack of any nerve injury but unmistakable chronic pain has led to increased interest in the role of glial cells in the maintenance of the neuropathic pain state (Watkins and Maier, Drug Disc. Today: Ther. Strategies 2004, 1:83-88; Watkins and Maier, Nat. Rev. Drug Discovery 2003, 2:973-985). More specifically, recent research has demonstrated that glial cells enhance the release of neurotransmitters which relay pain information to the spinal cord and, even more strikingly, release substances which increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses (Wieseler-Frank et al., Neurosignals 2005, 14:166-174). Blocking the activation of glial cells reduces pro-inflammatory cytokines and reverses pathological pain. To date, no therapeutics have been approved which have a putative glial cell-attenuation mechanism for the treatment of neuropathic pain. Molecules which are glial cell-attenuators may play an important role in the treatment of neuropathic pain.
In light of the above shortcomings in current approaches for treating chronic pain there exists a need for improved compositions and methods for treating pain, particularly neuropathic pain and its associated symptoms and, more specifically, neuropathic pain associated with certain conditions such as fibromyalgia, among others. Such approaches should ideally overcome one or more of the problems associated with existing methods for treating chronic pain.
Migraine is a disease condition characterized by episodes of head pain that is often throbbing and frequently unilateral, and can be severe. In migraine without aura, attacks are usually associated with nausea, vomiting or sensitivity to light, sound or movement. In some patients, migraine attacks are usually preceded or accompanied by transient focal neurological symptoms, which are usually visual; such patients are described as having migraine with aura.
Both migraine and epilepsy are usually included in the spectrum of neurological chronic disorders with episodic manifestations that are known to be characterized by recurrent attacks of nervous system dysfunction with a return to baseline between attacks.
The hypothesis of a possible clinical continuum between migraine and epileptic syndromes as entities resulting from altered neuronal excitability with a similar genetic basis has been postulated (Haut et al. Lancet Neurol 2006, 5:148-157). Epilepsy is a comorbid condition of migraine; it occurs more commonly in patients with migraine than in the general population, and the prevalence of migraine in epileptic patients is higher than in controls.
Some antiepileptic drugs (AEDs) are effective in the prevention of migraine (Rogawski et al Nat. Med. 2004, 10:685-692; Silberstein, S. D., Trends Pharmacol. Sci. 2006, 27:410-415). A rationale for this use is the hypothesis that migraine and epilepsy share several pathogenetic mechanisms.
Anxiety is broadly defined as a state of unwarranted or inappropriate worry often accompanied by restlessness, tension, distraction, irritability and sleep disturbances. This disproportionate response to environmental stimuli can hyper activate the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, resulting in somatic manifestation of anxiety, including shortness of breath, sweating, nausea, rapid heartbeat and elevated blood pressure (Sanford et al. Pharmacol. Ther. 2000, 88:197-212). Anxiety disorders represent a range of conditions and as a result have been classified into multiple distinct conditions, including generalized anxiety disorder (GAD), panic attack, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and social phobias (Sanford et al. Acta. Psychiatr. Scand. Suppl. 1998, 393:74-80).
Generalized anxiety disorder (GAD) is the most common of the anxiety disorders and is characterized by excessive and persistent worries. Some of the specific symptoms of GAD include restlessness, motor tension, difficulty concentrating, irritability, and sleep disturbances and the severity of the symptoms over time may be linked to the changing nature of the environmental stressor. With age, GAD symptoms become less severe.
Panic Disorder is a well-studied psychiatric condition that consists of multiple disabling panic attacks characterized by and intense autonomic arousal. In addition, heightened fear and anxiety states occur both during and between panic attacks. Approximately 3% of woman and 1.5% of men have panic attacks. During a panic attack, the individual experiences multiple symptoms including light-headedness, a pounding heart and difficulty in breathing. Panic disorder may be caused by an oversensitive brain system regulating autonomic functions.
Post-traumatic stress disorder (PTSD) is another example of a disorder associated with intense fear and anxiety states that require psychiatric treatment. PTSD results from exposure to a life threatening or traumatic event. Individuals with PTSD have recurring thoughts of the terrifying event. Reenactment of the event varies in duration from a few seconds or hours to several days. Individuals with major depression, with panic disorders or lacking strong social supports are vulnerable to develop PTSD.
Anxiety disorders, which occur in 10% to 30% of the population, represent not only a significant public health issue but place a substantial economic burden on society. A number of drugs have either been developed or are being developed for treating the different subclasses of anxiety. Some of these agents such as tricyclic antidepressants and β-adrenoreceptor antagonists found either limited use in treating specific disorders such as performance anxiety (e.g. β-adrenoreceptor antagonists suppression of the sympathetic manifestations of anxiety) or have fallen out of favor for reasons of efficacy and/or safety. Currently, direct and indirect serotonin receptor agonists (e.g. selective serotonin reuptake inhibitors (SSRI) and buspirone) and benzodiazepines are most often prescribed for treating anxiety disorders with benzodiazepine receptor agonist being a preferred therapeutic modality. The ability of benzodiazepines to enhance γ-aminobutyric acid (GABA) neurotransmission safely and rapidly is central to their effectiveness in treating anxiety disorder especially GAD and panic disorders (Stahl et al. J. Clin. Psychiatry 2002, 63: 756-757). Benzodiazepines act by positively modulating the inhibitory neurotransmitter GABA through an allosteric site on the GABA A receptor complex, a ligand-gated chloride ion channel. Nonetheless, the use of benzodiazepines is limited by side effects associated with enhanced GABAnergic neurotransmission, manifesting as sedation, muscle relaxation, amnesia and ataxia. Moreover, the potential for abuse and physical dependence is associated with the long-term use of benzodiazepines.
The following compound was reported to be active in the mouse electroshock seizure (MES) and pentylenetetrazole (PTZ) models of epilepsy (Bioorg. Med. Chem 2006; 14 (20), 6868; Eur. J. Med. Chem 2009; 44 (3), 1265):
